The present invention generally relates to the use of light therapy to destroy abnormal tissue in a tumor, and more specifically, to the use of multiple light sources disposed at spaced-apart treatment sites within a tumor to render the therapy.
Abnormal tissue in the body is known to selectively absorb certain dyes that have been perfused into a treatment site to a much greater extent than surrounding tissue. For example, tumors of the pancreas and colon may absorb two to three times the volume of these dyes, compared to normal tissue. Once pre-sensitized by dye tagging in this manner, the cancerous or abnormal tissue can be destroyed by irradiation with light of an appropriate wavelength or waveband corresponding to an absorbing wavelength or waveband of the dye, with minimal damage to normal tissue. This procedure, which is known as photodynamic therapy (PDT), has been clinically used to treat metastatic breast cancer, bladder cancer, lung carcinomas, esophageal cancer, basal cell carcinoma, malignant melanoma, ocular tumors, head and neck cancers, and other types of malignant tumors. Because PDT may selectively destroy abnormal tissue that has absorbed more of the dye than normal tissue, it can successfully be used to kill the malignant tissue of a tumor with less effect on surrounding benign tissue than alternative treatment procedures.
The effectiveness of PDT for treating tumors has become increasingly more evident to the medical community. Each year, numerous papers are published disclosing research that has been carried out to explore how PDT can more effectively be used and to better understand the processes by which PDT destroys abnormal cells. Much of the prior art discloses the use of relatively high powered lasers as an external light source employed to administer the light to a treatment site. Typically, the light from an external laser source is conveyed through an optical fiber to a treatment site on the skin of a patient or to an internal site within the patient""s body. Penetration of a tumor by the optical fiber is achieved either through a small incision in the overlying dermal layer, or directly, if the tumor is surgically exposed.
Most applications of PDT are conducted using a single optical fiber to provide the light therapy. An optical fiber used to render PDT may include a diffuser on its distal end to enhance the radial distribution of light from the fiber. Light emitted through the diffuser more fully illuminates a treatment site within a tumor in which the optical fiber has been inserted.
Research has been conducted to measure the penetration depth of light into tissue as a basis for assessing the volume of tissue that will be affected by the light applied to a treatment site to render PDT. This research has determined that the penetration depth (or a reciprocal value corresponding to the light attenuation of the tissue) depends upon the wavelength of the light, the type of tissue, the direction of irradiation, the oxygenation of the tissue, the striation of the tissue, the perfusion of blood in the tissue at the site, and other physiological and physical factors. Generally, at a wavelength of about 630 nm, the depth of penetration of light into tissue has been found to be between about 0.2 mm and 7 mm, depending upon the type of tissue (as reported in xe2x80x9cIn Vivo Measurement of the Optical Interaction Coefficients of Human Tumors at 630 nm,xe2x80x9d I. Driver, C. P. Lowdell, and D. V. Ash, Phys. Med. Biol., Vol. 36, No. 6, pp. 805-813, Table 3, (1991). Further, this paper reported a large inter-sample variation for the depth of light penetration in the same type of tissue. Tissue of a darker color, such as that of the liver, greatly attenuates light transmission, while brain tissue tends to scatter the light and thus limits light penetration. Generally, longer wavelength light penetrates more deeply, but most of the currently available photoreactive reagent dyes used for PDT have absorption wavebands in the 600-700 nm range.
The limited penetration depth of light in tissue would seem to indicate that light emitted at a single treatment site to render PDT will be effective in destroying abnormal tissue in only a relatively small volume within a tumor. To treat larger tumors, multiple light treatment sites would be expected to linearly expand the volume as a function of the number of light treatment sites used, i.e., the total volume of the effective zone in a tumor treated with the multiple optical fibers should be equal to the product of the volume treated at one site and the number of sites. In a paper entitled xe2x80x9cPhotodosimetry of Interstitial Light Delivery to Solid Tumors,xe2x80x9d M. C. Fenning, D. Q. Brown, and J. D. Chapman, Medical Physics, Vol. 21, No. 7, pp. 1149-1156 (July 1994), reported on research in which both anaplastic and well-differentiated Dunning prostate adenocarcinomas were illuminated in anesthetized Fisher X Copenhagen rats by light from single-fiber and multiple-fiber. illuminators. Each illuminator consisted of a 2 cm laterally diffusing optical fiber placed within a plastic brachytherapy needle implanted into a tumor. The radial falloff of intensity with distance from single fibers was used to determine light attenuation coefficients for various wavelengths, by employing a two-dimensional (2D) photodosimetry computer code. The coefficients were used to calculate relative light intensities in planes perpendicular to the single-fiber and various multiple-fiber configurations. Relative light intensities measured along tumor tracks were compared with those predicted by the 2D photodosimetry evaluation and were found to agree within xc2x114%, for all configurations of the optical fibers studied. It was noted that at wavelengths equal to and greater than about 700 nm, optical fiber spacings of at least one cm produced relatively uniform light fields (xc2x120%) in tumor planes perpendicular to the optical fibers. At line 32 of the second column on page 1155 of the paper, it is noted that:
For human tumors with light attenuating properties similar to the R3327-H tumor, the heterogeneity of light dose in tumor volumes delivered by a multifiber illuminator with 1.0-cm spacings will be considerably greater than xc2x120%. Illumination of tumors by such procedures will produce relatively large variations in biological effect by interstitial PDT. Furthermore, to expose all tumor tissue to a minimum light dose required for a specific biological effect, large fractions of the tumor would of necessity be overdosed. While this may not seriously impact upon tumor response, it will limit the volume of solid tumor which can be treated with a specific time by a specific light source. Laser output intensity has not been a limiting factor for the illumination of superficial lesions in clinical studies to date. Nevertheless, to successfully scale up this procedure for the treatment of bulky human tumors, laser output intensity and tumor volume will determine the time required to deliver a curative light dose.
The paper further concludes that more than seven optical fibers may be required to properly treat a tumor with PDT, to guarantee that adequate light is delivered, particularly to the periphery of a tumor, due to the rapid falloff of light at the edge of the illuminated field. The reference thus teaches or suggests that the effect of PDT on a human tumor, particularly one of larger size, will be limited to the region of the tumor directly viably illuminated by the plurality of optical fibers and implies that it will be necessary to repeat the treatment to different areas of the tumor by moving the plurality of the optical fibers so that direct illumination of a greater treatment volume can be accomplished.
The effects of PDT and the manner in which it destroys tissue are not clearly understood. It is believed that the primary mechanism by which PDT destroys cells relies upon the conversion of molecular oxygen to singlet oxygen and the release of free radicals by the light activated dye. In xe2x80x9cHow Does Photodynamic Therapy Work?xe2x80x9d by B. W. Henderson, and T. J. Dougherty, Photochemistry and Photobiology, Vol. 55, No. 1, pp. 145-157 (1992), it is noted that following the absorption of light, a sensitizer is transformed from its ground state to an excited triplet via a short-lived singlet state. The excited triplet can react directly either with a substrate or solvent by hydrogen atom or electron transfer to form radicals and radical ions (Type I reaction) or it can transfer its energy to oxygen directly to form singlet oxygen, which is a highly reactive species (Type II reaction). The paper states that indirect evidence suggests singlet oxygen is the major damaging species in PDT. Based on this belief, the reference concludes that PDT effects should be oxygen-dependent, with full effects of PDT being observed in vitro at oxygen concentrations of about 5%. It is reported by the reference that xe2x80x9cno photosensitization can be observed in the absence of measurable oxygen.xe2x80x9d Further, the reference teaches that the diffusion distance of singlet oxygen in cells is about 0.1 xcexcm, so that cell damage caused by singlet oxygen will occur close to its locus of generation. Singlet oxygen causes a loss of cell integrity by a photoperoxidation of membrane cholesterol and other unsaturated phospholipids. Associated with the cell membrane damage is a release of inflammatory and immune mediators. Also released through mast cell degranulation is histamine. The substances released are vasoactive, either constrictive or dilatory, and it is believed that they induce vascular damage. Tumor necrosis factor (TNF) is also released, and it too can cause vascular damage. The degree of vascular photosensitivity in tissue appears to be a function of the level of the circulating photoreactive agent. This reference reports that vascular damage in a tumor microenvironment induces hypoxic tumor cell fractions. A key conclusion stated in the paper is that the xe2x80x9crapid shift of cells into hypoxia [after PDT], where they are protected from further PDT damage due to the oxygen limitation of the photodynamic processes, is potentially limiting to direct tumor cell photodestruction.xe2x80x9d In essence, this statement indicates that efficacy of PDT in destroying tumor cells quickly diminishes after the light activation due to the self limiting effects of hypoxia caused by photovascular occlusion. In other words, the paper concludes that the resulting vascular occlusion limits further blood flow to the treatment site, which is necessary to supply additional molecular oxygen to the tumor cells for use in generating more singlet oxygen.
Also reported in the last cited reference is an observed infiltration of PDT-treated tissue with lymphocytes, plasma cells and histiocytes, which suggests an immune response to effects of the PDT. In high dose bladder PDT treatments, high levels of interleukin 1-beta, interleukin 2, and TNF-alpha have been observed in patients"" urine for up to 50 days following the therapy, concurrent with severe inflammatory symptoms. The relative extent of abnormal cell necrosis caused by generation of singlet oxygen and free radicals compared to that resulting from the immune response is not clear from the prior art.
It has been shown that illuminating abnormal cells, which have absorbed a photoreactive agent, with relatively low levels of light for extended periods of time may be even more effective in rendering PDT than the more conventional approach of using a high intensity laser light source to administer light for short time intervals. In commonly assigned U.S. Pat. No. 5,445,608, a plurality of transcutaneously implantable probes that include relatively low intensity light sources are disclosed for rendering PDT to treatment sites within a patient""s body. Such probes can be implanted interstitially within a tumor to administer PDT for many hours or days. As necessary, repetitive infusions of a suitable photoreactive agent can be made to sensitize the abnormal cells comprising the tumor so that they are susceptible to being destroyed by the PDT. An apparent question arises in regard to the efficacy of such an approach to treating a relatively large tumor. In view of the teaching of the art discussed above, one would be led to conclude that low intensity light sources on an interstitial probe would lack adequate penetration into a large tumor mass to treat more than a relatively small portion of the tumorxe2x80x94even if plural probes of this type were used. In addition, the prior art suggests that extended PDT delivered to a treatment site will not be effective in a large tumor due to the hypoxia resulting from vascular damage and the vasculature constriction that occurs soon after the PDT commences.
Application of PDT to a larger tumor would seem to require that a plurality of optical fibers spaced sufficiently close together and of sufficient number be inserted into the tumor to ensure that the light intensity between the optical fibers is substantially uniform throughout the volume of the tumor being treated. However, in view of the teaching of the prior art, implanting sufficient numbers of optical fibers or low light intensity probes to provide such uniform illumination does not seem to be a practical approach for treating a larger tumor. The expected effective zone of PDT would seem to be too limited due to the relatively shallow penetration of light into the tissue to justify the use of PDT to treat a large tumor.
Contrary to the suggestion of the prior art, it appears that PDT can be successfully used for treating larger tumor masses, and that the depth of light penetration into tumor tissue when effecting PDT is not so limiting as indicated in the prior art, in determining the true extent of the effectiveness of the therapy. Indeed, the effective zone of PDT in large tumors has been found to be much larger than the volume of the tumor into which light administered has previously been found to penetrate. Furthermore, the effectiveness of the PDT in treating a larger volume of a tumor appears to be more dependent upon a pattern in which light emitting sites are arrayed in the tumor than previously known.
In accord with the present invention, a method is defined for destroying abnormal tissue in a tumor within a patient""s body using an extended light therapy and at least one concomitant effect thereof. The method includes the step of administering a photoreactive agent to the abnormal tissue. The photoreactive agent, which has a characteristic absorption waveband, is preferably absorbed by the abnormal tissue rather than by normal tissue in the patient""s body. Light having a waveband corresponding to the absorption waveband of the photoreactive agent is administered to a treatment zone in the tumor. A pattern in which the light is administered to the tumor defines the treatment zone, and this zone preferably encompasses a substantial portion of the tumor not penetrated by the light being administered. The method provides for continuing to administer the light to the treatment zone for at least three hours of extended light therapy. The light destroys the abnormal tissue that it illuminates by activating the photoreactive agent absorbed thereby. Furthermore, the extended period of light therapy indirectly destroys the substantial portion of the tumor that is not penetrated by the light being administered by inducing at least one concomitant effect that destroys the abnormal tissue comprising the substantial portion of the tumor.
In one case, the concomitant effect arises because the destruction of the abnormal tissue in the treatment zone deprives the substantial portion of the tumor from receiving oxygen. The abnormal tissue in the substantial portion of the tumor is thus destroyed due to oxygen depletion.
In another instance, the concomitant effect arises because the photoreactive agent within the treatment zone that is activated by the light being administered diffuses into the substantial portion of the tumor that is not penetrated by the light. This photoreactive agent that is thus activated then destroys the abnormal tissue in the substantial portion of the tumor not directly penetrated by the light.
In yet another instance, the concomitant effect arises because the light therapy causes necrosis of the abnormal tissue in the treatment zone, which causes either an immune response or an inflammation in the patient""s body that destroys the abnormal tissue in the substantial portion of the tumor not directly penetrated by the light.
In still another instance, the concomitant effect arises because the destruction of abnormal tissue in the treatment zone causes either a vascular collapse, stasis, or occlusion, so that blood flow to the substantial portion of the tumor that is not directly penetrated by the light is terminated, causing the abnormal tissue in that substantial portion to die.
In one embodiment of the method, the light is administered through an optical fiber from a source that is external to the patient""s body. The method further preferably includes the step of implanting a plurality of probes for administering the light into the tumor at spaced-apart locations within the treatment zone. In one embodiment, the light is then administered from at least one light source included on each of the plurality of probes. In another embodiment, the light is delivered to the plurality of probes through a plurality of optical fibers from a source that is external to the patient""s body. The treatment zone is not more than about 3 cm from each of the plurality of probes.
In the method, the light administered to the treatment zone produces singlet oxygen, which depletes oxygen from the substantial portion of the tumor that is outside the treatment zone, causing a gradient of hypoxia and anoxia in that portion of the tumor, which leads to a destruction of the abnormal tissue contained therein.
The method may include further steps. Specifically, in one embodiment, the light is emitted into the tumor in a first direction from each of the plurality of probes, relative to the probe from which the light is emitted. Next, the method provides for terminating emission of light into the tumor in the first direction and emitting light into the tumor in a second direction from each of the plurality of probes. The second direction is substantially different from the first direction for each of the probes. Preferably, in one embodiment, the first direction is directed toward a perimeter of the tumor, and the second direction is directed toward an interior of the tumor. By first destroying the perimeter of the tumor, the interior portion of the tumor is more readily destroyed due to the one or more concomitant effects.